Farm and industrial workers who are exposed chronically to cholinesterase inhibitors have an elevated incidence of depression of the endogenous type. The proposed project will test the following hypotheses: 1) Depressive disorders ae related to an imbalance between cholinergic and noradrenergic neurotransmitter systems in the brain. 2) Depression is related to abnormal noradrenergic neuronal function which is secondary to increases in the number and/or affinity of presynaptic Alpha2 adrenoreceptors which are located upon nerve terminals. 3) Long-term exposure to cholinergic drugs (various types of cholinesterase inhibitors, and muscarinic and/or nicotinic receptor agonists) will lead to those changes in noradrenergic nerve function and in the sensitivity of Alpha2 adrenoreceptors which are thought to occur in depressive disorders. 4) Therapeutic agents and procedures which are effective in the treatment of major depressive disorder will reverse the changes in alpha2 adrenoreceptors and in noradrenergic nerve function which result from chronic exposure to cholinergic drugs. Changes in the function of alpha2 adrenergic receptors upon noradrenergic neurons will be evaluated in three different preparations: 1) superfused rat brain slices, 2) isolated rat left atrial strips and 3) isolated mouse vasa deferentia. The release of neurotransmitter during electrical stimulation of neurons in these preparations will be determined by measuring a) changes in the responses of the isolated muscle preparations, b) the efflux of endogenous neurotransmitter by a combination of high pressure liquid chromatography and electrochemical detection, c) the release of 3H-norepinephrine after incubating the tissues with 3H-dihydroxyphenylalanine and d) the release of dopamine beta hydroxylase, and enzyme which is released with norepinephrine but which is not taken back up into the neuron. Changes in the function of alpha2 adrenoreceptors on cholinergic neurons will be evaluated by changes in the responsiveness of the isolated guinea-pig ileal strip to coaxial field stimulation. Functional changes in adrenergic receptors on noradrenergic and cholinergic neurons will be correlated with changes in the binding of 3H-clonidine, 3H-yohimbine, 3H-prazosin, 3H-dihydroalprenolol and 3H-QNB to neuronal membranes isolated from various areas of the rat brain and to neuronal and non-neuronal membranes isolated from the heart and smooth muscle preparations.